Dye compositions and methods for film coating tablets and the like

ABSTRACT

An improved dye composition for use in coating tablets and the like is constituted by a stable, aqueous suspension containing a water-soluble, nontoxic dye, an opacifying agent which may be titanium dioxide or iron oxide an immobilizing agent for immobilizing the dye and preventing it from migrating when applied to a tablet or the like, the immobilizing agent being constituted by a nontoxic metal salt present in an amount of from approximately 0.1 to 10 equivalents of metal per mole of dye, and water. The suspension may also contain a film-forming, water-soluble or water-dispersible edible polymer and a plasticizer. These compositions are used in lieu of lake compositions to produce tablets and the like with uniform, non-mottled coatings.

This is a division of application Ser. No. 08/021,785, filed Feb. 24,1993, now U.S. Pat. No. 5,411,746.

BACKGROUND OF THE INVENTION

This invention relates to dye compositions and, more particularly, tostable, aqueous dye suspensions for use in film coating tablets and thelike to produce smooth, uniform, substantially non-mottled coatings.

Heretofore, it has been the practice to utilize FD&C lakes rather thanwater-soluble dyes as the materials of choice for coating tablets andthe like. The problems attending coating tablets with water-soluble dyeshas been noted in various patents and publications. For example, in anarticle entitled "Characterization Techniques for the Aqueous FilmCoating Process" by Mathur et al., Pharmaceutical Technology, October1984, it is noted that when water-soluble dyes are used in aqueous filmcoating, problems with color migration or mottling upon drying areencountered.

The dynamics of coating include the spreading of a thin wet layer of acoating suspension on a tablet which is dried rapidly after spreading.The drying dynamics usually lead to uneven distribution of awater-soluble dye in the dried layer. Though the color can be uniformlydistributed in the coating suspension and applied very uniformly on thetablet, a mottled appearance normally results when water-soluble dyesare used. This is believed to be due to the dye molecules migrating inthe film, being transported by the aqueous medium as it moves in thefilm layer surface and evaporates at distinct points. The dye thusaccumulates at these points producing dark patches or mottling.

The use of lakes has overcome these problems because they are insolublepigments which are manufactured by attaching dye molecules to aluminumhydroxide particles thereby rendering them water-soluble. These pigmentparticles or lakes are then dispersed in a coating suspension andapplied uniformly to the surface of a table to produce a uniformlycolored product because the pigment particles or lakes do not migrate inan aqueous medium.

Prior to 1960, it was the practice to sugar coat tablets and candieswith water-soluble dyes dissolved in sugar syrup. However, since thedevelopment of lakes in 1959, most sugar coating is carried out withlakes. Film coating of tablets and the like with water-soluble dyes hasnever been successfully achieved due to the difficulty of obtaininguniform coating because of migration of the dyes in an aqueous medium.

It has also been known to utilize mixtures of lakes and water-solubledyes in coating suspensions with the dyes being incorporated to reducethe coat and to obtain brighter color shades.

Because water-soluble dyes are less costly than lakes, it would beadvantageous if such dyes could be used in coating suspensions in lieuof lakes while yet providing uniform, non-mottled coatings.

SUMMARY OF THE INVENTION

Among the objects of the present invention may be noted the provision ofstable, aqueous suspension compositions which contain water-soluble dyesas the color component for coating tablets and the like; the provisionof such compositions which further contain metal salt immobilizingagents to prevent the water-soluble dyes from migrating when applied totablets and the like; the provision of such compositions which areeconomically advantageous in requiring less color to be utilized inachieving the same color effect; the provisions of compositions of thistype which permit the production of coatings for tablets and the likewhich are smooth uniform and non-mottled and have more gloss and lessbrittleness than coatings produced with lakes; and the provision ofmethods of producing such smooth, uniform and non-mottled coatings ontablets and the like. Other objects and features will be in partapparent and in part pointed out hereinafter.

Briefly, the present invention is directed to a stable, aqueoussuspension for use in preparing a coating composition for coatingtablets and the like which comprises a water-soluble dye, an opacifyingagent which may be titanium dioxide or iron oxide, a nontoxicimmobilizing agent for immobilizing the dye and preventing it frommigrating when applied to a tablet or the like, the nontoxicimmobilizing agent being constituted by a nontoxic metal salt present inan amount of from approximately 0.1 to approximately 10 equivalents ofmetal per mole of dye, and water. Optionally, the composition may alsocontain a fluidizing agent. The invention is further directed to theabove-noted suspension composition additionally containing afilm-forming, water-soluble or water-dispersible, edible polymer such ashydroxypropylmethyl cellulose.

The invention, in another embodiment, is directed to a stable, aqueoussuspension composition for use in preparing a coating composition forcoating tablets and the like which comprises a water-soluble, nontoxicdye, an FD&C or D&C lake, the proportion by weight of lake to dye beingin the range of approximately 1:1 to approximately 1:10, an opacifyingagent, a fluidizing agent such as ethylene diamine tetraacetic acid, andwater.

In still another embodiment, the invention is directed to a stable, dryconcentrate for use in preparing an aqueous suspension which has thesame composition set out above for the aqueous suspension but containsno water. The dry concentrate may also contain a fluidizing agent, afilm-forming, water-soluble or water-dispersible edible polymer and aplasticizer.

In yet another embodiment, the invention is directed to the method ofproducing a smooth, uniform, substantially non-mottled coating ontablets and the like by preparing the above-described aqueous suspensioncomposition containing a nontoxic immobilizing metal salt, mixing thesuspension with an aqueous solution of a film-forming, water-soluble orwater-dispersible, edible polymer to form a coating suspension, and thenapplying the coating suspension onto tablets or the like whereby thenontoxic immobilizing agent immobilizes the water-soluble dye andsubstantially prevents it from migrating, thereby producing a smooth,uniform, substantially non-mottled coating on the tablets or the like.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, it has now been found thatnontoxic, water-soluble dyes may be advantageously employed in lieu oflakes in the coating of tablets, candy pieces, nuts, seeds, capsules orgranules by incorporating in the coating composition with such a dye animmobilizing agent which renders the dye insoluble or less mobile andsubstantially prevents it from migrating in the coating layer afterapplication to a tablet or the like. This consequent immobilization ofthe dye, unexpectedly achieved through the present invention, preventsthe classic mottling phenomenon encountered in the past when the use ofwater-soluble dyes produced unacceptable, uneven and mottled color inthe coating of tablets and the like.

The immobilizing agent in accordance with the invention is a nontoxicmetal salt which is present in the coating suspension in an amount fromapproximately 0.1 to approximately 10 equivalents of metal per mole ofthe water-soluble dye. More optimally, the best results are achievedwhen the ratio is approximately 0.5 to approximately 5 equivalents ofmetal per mole of dye, and more preferably 1 equivalent of metal permole of dye. Any nontoxic metal salt may be employed and illustrativemetal salts include alkaline earth metal salts, iron salts, aluminumsalts and zinc salts. Among the preferred alkaline earth metals arecalcium and magnesium, and such metals may be employed in the presentinvention in the form of chloride, acetate, nitrate, oxide, hydroxide,carbonate, sulfate, phosphate, silicate or other salts. The metal saltused may be either water-soluble or water-soluble, but it must besubstantially nontoxic. A source of metal salt, such as talc or clay,may also be employed with the proportion of equivalents of metal permole of the water-soluble dye being in the ranges described above.

The invention may be practiced to achieve the production of smooth,uniform, substantially non-mottled coatings with any nontoxic,water-soluble dye or mixture of two or more such dyes. The nontoxic,water-soluble dye may be and FD&C dye, such as FD&C Red 40, FD&C Yellow5, FD&C Yellow 6, a D&C dye or a natural colorant such as annatto orother natural colorant which exists in salt form.

In the practice of the invention, a stable, aqueous suspensioncomposition is formulated by combining a water-soluble, nontoxic dye, ametal salt immobilizing agent, with the proportion of metal salt to dyebeing within the above-described ranges, an opacifying agent which maybe either titanium dioxide or iron oxide, and water. This initialsuspension composition may be formulated, for example, by adding thenontoxic, water-soluble dye or mixture of dyes and the immobilizingagent to a dispersion of titanium dioxide in water. The quality of thefinal coating obtained may be further improved by incorporating into thesuspension composition fluidizing agent such as ethylene diaminetetraacetic acid, diethylene trimine pentaacetic acid, dehydroxyethylglycine, nitrilo triacetic acid, hydroxyethylene diamine triacetic acid,iminodiacetic acid or ethanol diglycine.

To prepare the coating suspension for use in film coating tablets andthe like, the above-formulated suspension composition is added to anaqueous solution of a film-forming, water-soluble or water-dispersible,edible polymer. Polymers of this type useful in the invention includemethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, maltodextrin, polydextrose, modifiedstarches (such as "Purity Gum 59" Marketed by National Starch) andnatural gums such as gum tragacanth, gum acacia and xanthan gum. Otherconventionally employed polymers and resins of this type may beemployed, and mixtures of such polymers may also be used.Hydroxypropylmethyl cellulose is the preferred polymer of this type foruse in the practice of the invention. The aqueous solution of suchpolymer to which the suspension composition is added may also contain aplasticizer such as glycerin, propylene glycol, polyethylene glycol orothers known to the art. These components may be stirred together, forexample, with a magnetic stirrer (low energy) for a short period of time(e.g. 2 minutes) whereupon the coating suspension is ready for coatingtablets and the like.

It should be further noted that since the present invention enables theuse of water-soluble dyes, a coating suspension can be directly preparedby incorporating the requisite film-forming, water-soluble orwater-dispersible polymer into the above-described suspensioncomposition and thereby produce a coating suspension ready for use inthe coating of tablets and the like without additional process steps.

The coating suspension is sprayed onto tablets or the like inconventional manner and produces a smooth, uniform, glossy andnon-mottled coating as a result of the nontoxic immobilizing agentimmobilizing the water-soluble dye and preventing it from migrating inthe coating layer. The practice of the invention not only enables such adesirable coating to be achieved more efficiently and economically, butof equal importance, less color is required to produce the same effectas realized with lakes. Additionally, the elimination of bulky lakepigments from tablet coatings enables the coating suspensions of thepresent invention to provide more gloss to film coatings and lessbrittleness to both film and sugar coatings. In this regard, it shouldbe noted that the present invention may be practiced with sugarsolutions in which embodiment the initial suspension compositiondescribed above is added to a sugar solution containing no film-formingpolymer and the resulting coating suspension applied to candy orpharmaceutical dosage forms to produce smooth, uniform, substantiallynon-mottled coatings.

In another but less preferred embodiment of the invention, the inventioncan be carried out using a mixture of a nontoxic, water-soluble dye anda lake as the coloring agent, with the lake functioning as a source ofaluminum metal salt. When such a mixture is utilized, it has been foundthat the proportion by weight of lake to dye in the mixture must be inthe range of approximately 1:1 to approximately 1:10, with a preferredrange being on the order of approximately 1:4. Also, when employing amixture of dye and lake where the lake constitutes more than 10% byweight of the composition, the suspension composition must alsoincorporate a fluidizing agent in order to maintain the mixture in afluid state. Any of the fluidizing agents set forth above may be usedfor this purpose.

As an additional feature of the invention, dry concentrates of theabove-described suspension compositions and coating suspensions may beprepared by dry mixing of the various components. The dry concentratecompositions can then simply be added to the requisite amount of waterto form the corresponding suspension compositions or coating suspensionsfor use in direct coating of tablets and the like in accordance with theinvention.

The following examples illustrate the practice of the invention.

EXAMPLE 1

A stable, aqueous suspension was prepared having the followingcomposition:

    ______________________________________                                        Component             Wt.                                                     ______________________________________                                        FD&C Red 40 dye       18.0 g.                                                 TiO.sub.2             18.0 g.                                                 Calcium chloride      2.0 g.                                                  Water                 62.0 g.                                                                       100.0 g.                                                ______________________________________                                    

The dye and calcium chloride immobilizing agent were added to an aqueousdispersion of titanium dioxide with the composition containing 1equivalent of calcium per mole of dye.

EXAMPLE 2

A coating suspension was prepared having the following composition:

    ______________________________________                                        Component               Wt.                                                   ______________________________________                                        Methocel E-5 (10%)      80.0 g.                                               Polyethylene glycol (PEG-400)                                                                         1.6 g.                                                Suspension of Example 1 3.0 g.                                                Water                   15.4 g.                                                                       100.0 g.                                              ______________________________________                                    

The above ingredients or components were stirred together with amagnetic stirrer and the coating suspension was ready for coating in 2minutes. The coating suspension was sprayed onto 420 g. of tablets and abright, smooth, uniform, glossy coating resulted. The coating resultedin a highly desirable, elegant tablet.

EXAMPLE 3

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 6 dye        19.3 g.                                              TiO.sub.2                19.3 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Calcium chloride         1.9 g.                                               Water                    59.1 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 4

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 6 dye        19.5 g.                                              TiO.sub.2                19.5 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Magnesium chloride       1.9 g.                                               Water                    58.7 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 5

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 6 dye        19.3 g.                                              TiO.sub.2                19.3 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Calcium carbonate        1.9 g.                                               Water                    59.1 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 6

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.4 g.                                              TiO.sub.2                18.7 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Magnesium carbonate      1.9 g.                                               Water                    59.5 g.                                              ______________________________________                                    

EXAMPLE 7

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        18.3 g.                                              TiO.sub.2                17.0 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Pharmasorb clay          4.7 g.                                               Water                    59.5 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 8

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Red 40 dye          18.5 g.                                              TiO.sub.2                17.8 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Bentonite clay           3.7 g.                                               Water                    59.6 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 9

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Red 40 dye          19.3 g.                                              TiO.sub.2                18.6 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Calcium carbonate        1.9 g.                                               Water                    59.8 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 10

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.0 g.                                              TiO.sub.2                19.0 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Alumina                  1.9 g.                                               Water                    59.7 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 11

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 6 dye        18.4 g.                                              TiO.sub.2                18.4 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Aluminum chloride (28%)  3.4 g.                                               Water                    59.4 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 12

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.1 g.                                              TiO.sub.2                19.1 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Zinc oxide               1.9 g.                                               Water                    59.5 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 13

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.6 g.                                              TiO.sub.2                19.6 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Aluminum chloride (28%)  3.6 g.                                               Water                    59.8 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 14

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.0 g.                                              TiO.sub.2                19.0 g.                                              Ethylene diamine tetraacetic acid                                                                      0.4 g.                                               Barium sulfate           1.9 g.                                               Water                    59.7 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 15

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component             Wt.                                                     ______________________________________                                        FD&C Yellow 5 dye     19.4 g.                                                 TiO.sub.2             19.4 g.                                                 Calcuim carbonate     2.0 g.                                                  Water                 60.2 g.                                                                       100.0 g.                                                ______________________________________                                    

The compositions of Examples 3 through 15 were used as described inExample 2 to produce tablets with a smooth, uniform, substantiallynon-mottled coating.

EXAMPLE 15

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Red 40 dye          15.0 g.                                              FD&C Red 40 dye lake     15.0 g.                                              TiO.sub.2                18.0 g.                                              Ethylene diamine tetraacetic acid                                                                      0.5 g.                                               Water                    71.5 g.                                                                       120.0 g.                                             ______________________________________                                    

In this composition, the incorporation of ethylene diamine tetraaceticacid is essential to keep the composition fluid. Twenty percent more ofthis composition is required to achieve the same color level as with thecomposition of Example 1.

EXAMPLE 17

A stable, dry concentrate composition was prepared by mixing thefollowing:

    ______________________________________                                        Component              Wt.                                                    ______________________________________                                        FD&C Yellow 5 dye      46.0 g.                                                TiO.sub.2              46.0 g.                                                CaCl.sub.2.2H.sub.2 O  8.0 g.                                                                        100.0 g.                                               ______________________________________                                    

EXAMPLE 18

A stable, dry concentrate composition was prepared by mixing thefollowing:

    ______________________________________                                        Component               Wt.                                                   ______________________________________                                        FD&C Red 40 dye         46.0 g.                                               TiO.sub.2               46.0 g.                                               Calcium carbonate       6.5 g.                                                Calcium disodium ethylene                                                                             0.5 g.                                                diamine tetraacetate                                                                                  100.0 g.                                              ______________________________________                                    

EXAMPLE 19

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.0 g.                                              Cos. Iron oxide Yellow   1.9 g.                                               TiO.sub.2                19.0 g.                                              Ethylene diamine tetraacetic acid                                                                      1.1 g.                                               Water                    59.0 g.                                                                       100.0 g.                                             ______________________________________                                    

EXAMPLE 20

A stable, aqueous suspension was prepared as in Example 1 having thefollowing composition:

    ______________________________________                                        Component                Wt.                                                  ______________________________________                                        FD&C Yellow 5 dye        19.5 g.                                              TiO.sub.2                19.5 g.                                              Ethylene diamine tetraacetic acid                                                                      1.1 g.                                               Dicalcium phosphate      1.0 g.                                               Water                    59.9 g.                                                                       100.0 g.                                             ______________________________________                                    

The compositions of Examples 19 and 20 when used as described in Example2 produced tablets with smooth, uniform, non-mottled coatings.

In view of the above, it will be seen that the several objects of theinvention are achieved and other advantageous results obtained.

As various changes could be made in the above compositions and methodswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:
 1. A stable, dry concentrate composition for use inpreparing a stable, aqueous suspension composition comprising:(i) awater-soluble, nontoxic dye, (ii) an opacifying agent selected from thegroup consisting of titanium dioxide and iron oxide, and (iii) anontoxic immobilizing agent, said nontoxic immobilizing agent beingconstituted by a nontoxic metal salt present in an amount fromapproximately 0.1 to approximately 10 equivalents of metal per mole ofsaid dye.
 2. A stable, dry concentrate composition as set forth in claim1 wherein said nontoxic metal salt is present in an amount of fromapproximately 0.5 to approximately 5 equivalents of metal per mole ofsaid dye.
 3. A stable, dry concentrate composition as set forth in claim1 wherein said nontoxic metal salt is selected from the group consistingof alkaline earth metal salts, iron salts, aluminum salts and zincsalts.
 4. A stable, dry concentrate composition as set forth in claim 1wherein said nontoxic metal salt is selected from the group consistingof calcium and magnesium salts.
 5. A stable, dry concentrate compositionas set forth in claim 1 wherein said opacifying agent is titaniumdioxide.
 6. A stable, dry concentrate composition as set forth in claim1 wherein said water-soluble, nontoxic dye is selected from the groupconsisting of water-soluble FD&C and D&C dyes.
 7. A stable, dryconcentrate composition as set forth in claim 1 wherein said compositionadditionally includes a fluidizing agent selected from the groupconsisting of ethylene diamine tetraacetic acid, diethylene triaminepentaacetic acid, dihydroxyethyl glycine, nitrilo triacetic acid,hydroxyethylene diamine triacetic acid, iminodiacetic acid and ethanoldiglycine.
 8. A stable, dry concentrate composition for use in preparinga coating suspension for coating tablets and the like comprising thestable, dry concentrate composition of claim 1 and a film-forming,water-soluble or water-dispersible, edible polymer.
 9. A stable, dryconcentrate composition as set forth in claim 8 wherein said polymer isselected form the group consisting of methyl cellulose,hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, maltodextrin, polydextrose, modified starches and a naturalgum selected from the group consisting of gum tragacanth, gum acacia andxanthan gum.
 10. A stable, dry concentrate composition as set forth inclaim 8 wherein said polymer is hydroxypropylmethyl cellulose.
 11. Astable, dry concentrate composition as set forth in claim 8 wherein saidcomposition additionally includes a plasticizer.
 12. The composition ofclaim 1 in which the nontoxic immobilizing agent is applied to an objectselected from the group consisting of tablets, candy pieces, nuts,seeds, capsules and granules.